Natural killer receptor-mediated regulation of dendritic cell functions in chronic hepatitis C

自然杀伤细胞(NK)是一种特殊的淋巴细胞，通过其杀死病原体感染细胞和转化细胞的能力提供第一道防线。NK细胞的功能由一系列不同的细胞表面受体介导的抑制和激活信号的精细平衡来调节。我们最近发现慢性丙型肝炎患者NK细胞表面抑制受体CD94/NKG2A的表达上调，NKG2A的配体HLAE在所有受试的人肝癌细胞系和未转化的肝细胞中都有表达，但在经典的NK敏感靶点K562细胞中不表达。从慢性丙型肝炎患者分离的NK细胞杀伤肝癌细胞的能力和产生干扰素γ的能力低于健康献血者，而NK细胞对K562细胞的反应性无显著差异。值得注意的是，单核细胞来源的树突状细胞的成熟和激活在存在丙型肝炎病毒-NK细胞和肝癌细胞的情况下受到负调控，在丙型肝炎病毒-NK细胞和肝癌细胞共培养过程中加入抗NKG2A抗体可以恢复这种调节。研究表明，树突状细胞通过Toll样受体监测病原体相关的分子模式，识别来自微生物的危险信号。我们的发现揭示了NK受体是将危险信号从异常细胞传递到免疫系统的重要接口。CD94/NKG2A的异常表达可能对慢性丙型肝炎患者对感染或转化的细胞的先天抵抗和随后的获得性免疫产生负面影响。

Natural kilier (NK) cells are specialized lymphocytes that provide a first line of defense through their ability to kill pathogen-infected cells and transformed cells. The function of NK cells is regulated by a fine balance of inhibitory and activating signals, which are mediated by a diverse array of cell-surface receptors. We recently found that expression of the inhibitory receptor CD94/NKG2A is upregulated on NK cells in patients with chronic hapatitis C. HLA-E, a ligand for NKG2A, was expressed in all human hepatoma cell lines tested as well as non-transformed hepatocytes, but not in K562 cells, a classical NK-sensitive target. NK cells isolated from patients with chronic hepatitis C (HCV-NK) were less capable of killing hepatoma cells and of producing IFNγ in response to hepatoma cells than those from healthy donors, whereas there was no significant difference in NK responsiveness towards K562 cells. Of note is the finding that maturation and activation of monocyte-derived dendritic cells were negatively modulated in the presence of HCV-NK and hepatoma cells, which was restored by the addition of anti-NKG2A antibody during the coculture of HCV-NK and hepatoma cells. Research revealed that dendritic cells recognize danger signals from microorganisms by monitoring pathogen-associated molecular patterns via Toll-like receptors. Our findings have shed light on NK receptors as an important interface that transmits danger signals from abnormal cells to immune systems. Aberrant expression of CD94/NKG2A should have negative impact on innate resistance and subsequent adaptive immunity towards HCV-infected or transformed cells in chronic hepatitis C.